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OBJECTIVES: The aim of this study was to review epidemiologic evidence, provide summary risk estimates of the association between exposure to chlorination disinfection by-products (DBPs) and congenital anomalies, and provide recommendations for future studies. DATA SOURCES AND EXTRACTION: We included all published epidemiologic studies that evaluated a relationship between an index of DBP exposure (treatment, water source, DBP measurements, and both DBP measurements and personal characteristics) and risk of congenital anomalies. When three or more studies examined the same exposure index and congenital anomaly, we conducted a meta-analysis to obtain a summary risk estimate comparing the highest exposure group with the lowest exposure group. When five or more studies examined total trihalomethane (TTHM) exposure and a specific congenital anomaly, we conducted a meta-analysis to obtain exposure-response risk estimates per 10 microg/L TTHM. DATA SYNTHESIS: For all congenital anomalies combined, the meta-analysis gave a statistically significant excess risk for high versus low exposure to water chlorination or TTHM [17%; 95% confidence interval (CI), 3-34] based on a small number of studies. The meta-analysis also suggested a statistically significant excess risk for ventricular septal defects (58%; 95% CI, 21-107), but this was based on only three studies, and there was little evidence of an exposure-response relationship. We observed no statistically significant relationships in the other meta-analyses. We found little evidence for publication bias, except for urinary tract defects and cleft lip and palate. CONCLUSION: Although some individual studies have suggested an association between chlorination disinfection by-products and congenital anomalies, meta-analyses of all currently available studies demonstrate little evidence of such an association. ; This work was conducted without specific allocated funding, but contributions were made by researchers working on the Integrated Assessment of Health Risks of Environmental Stressors in Europe (INTARESE) project, cofunded by the European Commission under the Sixth Framework Programme (2002–2006), and the Health Impacts of Long-term Exposure to Disinfection By-products in Drinking Water in Europe (HIWATE) project, which is a 3.5-year Specific Targeted Research Project funded under the European Union Sixth Framework Programme for Research and Technological Development by the Research Directorate–Biotechnology, Agriculture and Food Research Unit (contract Food-CT-2006-036224)

Exposure to environmental pollutants, particularly during pregnancy, can have adverse consequences on child development but little is known about the effects of pollutant mixtures on endogenous metabolism in pregnant women. We aimed to identify urinary metabolic signatures associated with low level exposure to multiple environmental pollutants in pregnant women from the INMA (INfancia y Medio Ambiente) birth cohort (Spain, N = 750). 35 chemical exposures were quantified in first trimester blood samples (organochlorine pesticides, PCBs, PFAS), in cord blood (mercury), and twice in urine at 12 and 32 weeks of pregnancy (metals, phthalates, bisphenol A). 1H nuclear magnetic resonance (NMR) metabolic profiles of urine were acquired in the same samples as pollutants. We explored associations between exposures and metabolism through an exposome-metabolome wide association scan and multivariate O2PLS modeling. Novel and reproducible associations were found across two periods of pregnancy for three nonpersistent pollutants and across two subcohorts for four of the persistent pollutants. We found novel metabolic signatures associated with arsenic exposure: TMAO and dimethylamine possibly related to gut microbial methylamine metabolism and homarine related to fish intake. Tobacco smoke exposure was related to coffee metabolism and PCBs with 3-hydroxyvaleric acid, usually released under ketoacidosis. These findings will have implications for further understanding of maternal-fetal health, and health across the life-course. ; This work was supported by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 308333–the HELIX project, the Medical Research Council Integrative Toxicology Training Partnership (ITTP) through a PhD studentship (recipient LM), an MRC-ITTP career development fellowship (recipient MC), an MRC early career fellowship (recipient OR), and the Medical Research Council–Public Health England (MRC-PHE) Centre for Environment and Health (MR/L01341X/1). The subcohort studies were funded by grants from Instituto de Salud Carlos III (Red INMA G03/176, FIS-PI06/0867, FIS-PS09/00090 and FIS-PI13/02187), Generalitat de Catalunya-CIRIT 1999SGR 00241, Department of Health of the Basque Government (2005111093, 2009111069, and 2013111089), and the Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001). Convenios anuales con los ayuntamientos de la zona del estudio (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain). We thank Olivier Cloarec and Ekaterina (Katya) Nevedomskaya for developing the in-house script to perform O2PLS models.